KEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancer
Name
Krail-2017-KEAP1 loss modulates sensitivity to.pdf
Size
1.03 MB
Format
Adobe PDF
Checksum (MD5)
e0858aece4e0505f3888afe1509d6569
Author(s)
Krall, Elsa B
Munoz, Diana M
Ilic, Nina
Niederst, Matthew J
Yu, Kristine
Ruddy, David A
Redig, Amanda J
Gainor, Justin F
Williams, Juliet A
Asara, John M
Date Issued
February 2017
Journal
eLife
Publisher
eLife Sciences Publications, Ltd.
Citation
Krall, Elsa B; Wang, Belinda; Munoz, Diana M; Ilic, Nina; Raghavan, Srivatsan; Niederst, Matthew J; Yu, Kristine et al. “KEAP1 Loss Modulates Sensitivity to Kinase Targeted Therapy in Lung Cancer.” eLife 6 (February 2017): e18970 © 2017, Krall et al
Version
Final published version
Abstract
nhibitors that target the receptor tyrosine kinase (RTK)/Ras/mitogen-activated protein kinase (MAPK) pathway have led to clinical responses in lung and other cancers, but some patients fail to respond and in those that do resistance inevitably occurs (Balak et al., 2006; Kosaka et al., 2006; Rudin et al., 2013; Wagle et al., 2011). To understand intrinsic and acquired resistance to inhibition of MAPK signaling, we performed CRISPR-Cas9 gene deletion screens in the setting of BRAF, MEK, EGFR, and ALK inhibition. Loss of KEAP1, a negative regulator of NFE2L2/NRF2, modulated the response to BRAF, MEK, EGFR, and ALK inhibition in BRAF-, NRAS-, KRAS-, EGFR-, and ALK-mutant lung cancer cells. Treatment with inhibitors targeting the RTK/MAPK pathway increased reactive oxygen species (ROS) in cells with intact KEAP1, and loss of KEAP1 abrogated this increase. In addition, loss of KEAP1 altered cell metabolism to allow cells to proliferate in the absence of MAPK signaling. These observations suggest that alterations in the KEAP1/NRF2 pathway may promote survival in the presence of multiple inhibitors targeting the RTK/Ras/MAPK pathway.
MIT Department
Broad Institute of MIT and Harvard
Terms of Use
Creative Commons Attribution 4.0 International License
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.7554/eLife.18970
